1. Field of the Invention
This invention relates to a novel class of peptidyl derivatives of aromatic diesters of .alpha.-aminoalkylphosphonic acids useful for selectively inhibiting elastase, selectively inhibiting chymotrypsin-like enzymes and selectively inhibiting trypsin-like enzymes. The diesters of .alpha.-aminoalkylphosphonic acids are analogues of natural .alpha.-amino acids. This invention is also relates to a method for controlling tumor invasion, treating inflammation and controlling blood coagulation in patients using the novel compounds of the present invention. We have found that peptidyl derivatives of aromatic diesters of .alpha.-aminoalkylphosphonic acids are potent inhibitors of chymotrypsin-like enzymes, elastases, blood coagulation enzymes, tryptases, kaliikreins, and other serine proteases, and therefore they are useful as anti-tumor, anti-inflammatory and anticoagulant agents.
2. Description of the Related Art
Serine proteases play critical roles in several physiological processes such as digestion, blood coagulation, complement activation, fibrinolysis, and reproduction. Serine proteases are not only a physiological necessity, but also a potential hazard if they are not controlled. Blood coagulation serine proteases are responsible for vascular clotting, cerebral infarction and coronary infarction. Chymotrypsin-like enzymes and plasmin are involved in tumor invasion, tissue remodeling, and clot dissociation. Uncontrolled proteolysis by other serine proteases such as elastase may cause pancreatitis, emphysema, rheumatoid arthritis, inflammation and adult respiratory distress syndrome. Accordingly, specific and selective inhibitors of these proteases should be potent anticoagulants, anti-inflammatory agents and anti-tumor agents useful in the treatment of protease-related diseases (Powers and Harper, in Proteinase Inhibitors, Barrett and Salvesen, eds., Elsevier, 1986, pp. 55-152; Tryggvason, Hoyhtya and Salo, Biochem. Biophys. Acta, 1987, 907, 191-217, incorporated herein by reference). In vitro proteolysis by trypsin, chymotrypsin or the elastase family is a serious problem in the production, purification, isolation, transport or storage of peptides and proteins.